Growth Retardation, Developmental Delay, And Facial Dysmorphism

A number sign (#) is used with this entry because of evidence that growth retardation, developmental delay, and facial dysmorphism (GDFD) is caused by homozygous mutation in the FTO gene (610966) on chromosome 16q12.

Description

Growth retardation, developmental delay, and facial dysmorphism (GDFD) is an autosomal recessive multiple congenital anomaly syndrome characterized by severe psychomotor retardation, poor overall growth, and dysmorphic facial features. Additional features may include cardiac malformations and deafness (summary by Daoud et al., 2016).

Clinical Features

Boissel et al. (2009) reported a consanguineous Palestinian Arab family in which 9 individuals had a severe multiple congenital anomaly syndrome with death by age 3 years. Clinical features included coarse face with anteverted nostrils, thin vermilion border, prominent alveolar ridge, retrognathia, and protruding tongue. All had severe failure to thrive in infancy, and 3 had intrauterine growth retardation. Six patients had heart defects, including ventricular septal defect, atrioventricular defect, and patent arteriosus, and 4 had hypertrophic cardiomyopathy. All showed severe developmental delay and microcephaly variably combined with lissencephaly, seizures, or Dandy-Walker malformation. Other features included short neck, brachydactyly, toenail hypoplasia, neurosensory deafness, umbilical hernia, hypertrophy of the labia, undescended testes, cleft palate, and optic disc abnormalities. Cultured skin fibroblasts from 1 patient showed altered morphology with increased number of vacuoles and cellular debris and decreased life span, suggesting premature senescence.

Daoud et al. (2016) reported a 21-month-old girl, born of consanguineous Tunisian parents, with a severe congenital anomaly syndrome characterized by growth retardation, failure to thrive, and severely delayed global development with lack of speech. Dysmorphic facial features included periorbital fullness, broad nasal bridge, anteverted nares, smooth long philtrum, thin upper vermilion border, wide mouth, and small chin. Additional features included patent ductus arteriosus, left ventricular hypertrophy with hypertrabeculation of the left ventricular apex, cutis marmorata, and hearing loss. Brain imaging showed decreased brain parenchyma, delayed myelination, and a thin corpus callosum.

Molecular Genetics

By genomewide linkage analysis, followed by candidate gene sequencing, in a consanguineous Palestinian family with severe growth retardation, developmental delay, and facial dysmorphism, Boissel et al. (2009) identified a homozygous mutation in the FTO gene (R316Q; 610966.0001).

In a 21-month-old girl, born of consanguineous Tunisian parents, with growth retardation, developmental delay, and facial dysmorphism, Daoud et al. (2016) identified a homozygous missense mutation in the FTO gene (S319F; 610966.0002). The mutation was found by targeted next-generation sequencing and confirmed by Sanger sequencing. In vitro functional expression studies showed that the mutant protein did not refold completely after thermal denaturation, had decreased demethylation activity, and had decreased 2-oxoglutarate (2OG) turnover compared to wildtype. The findings were consistent with low levels of residual enzyme activity. Skin fibroblasts derived from the patient did not show decreased proliferative ability or premature senescence, as had been observed by Boissel et al. (2009), suggesting that the S319F mutation reduced, but did not completely ablate, enzymatic activity.